Aldosterone and Cardiovascular Disease: Research and Mentoring Program

醛固酮和心血管疾病：研究和指导计划

基本信息

批准号：
9314760
负责人：
Gail Kurr Adler
金额：
$ 12.15万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-02 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9314760
关键词：
Address Aldosterone Anti-Retroviral Agents Applications Grants Area Atherosclerosis Biological Markers Biology Blood Vessels CCL2 gene Cardiac Cardiomyopathies Cardiovascular Abnormalities Cardiovascular Diseases Cardiovascular system Clinical Investigator Complement Coronary Data Diabetes Mellitus Disease Double-Blind Method Educational process of instructing FDA approved Fibrosis Functional disorder Funding Galectin 3 Generations Grant HIV Heart Diseases High Prevalence Hormones IL6 gene Image Imaging Techniques Imaging technology Immunologic Markers Impairment Individual Inflammation Inflammation Mediators Injury Insulin Resistance Investigation LCN2 gene Link Magnetic Resonance Imaging Measures Mentors Metabolic Metabolic Diseases Mineralocorticoid Receptor Modeling Morbidity - disease rate Morphology Myocardial Myocarditis Obesity Outcome Pathologic Patients Pharmaceutical Preparations Physicians Placebos Plasma Population Positron-Emission Tomography Radiology Specialty Randomized Receptor Activation Renin Renin-Angiotensin-Aldosterone System Research Research Personnel Risk Risk Factors Risk Reduction Role Sum Techniques Testing Time Training Training Support Vascular Diseases Visceral antiretroviral therapy burden of illness cardiotrophin 1 cardiovascular disorder risk cardiovascular imaging cardiovascular injury cardiovascular risk factor coronary computed tomography angiography coronary fibrosis diabetes control disorder risk double-blind placebo controlled trial effective therapy eplerenone experience extracellular high risk immune activation improved indexing inflammatory marker insight interest mortality multidisciplinary novel patient oriented patient oriented research procollagen Type III-N-terminal peptide programs randomized placebo controlled trial treatment strategy vascular inflammation virology

项目摘要

PROJECT SUMMARY/ABSTRACT This K24 competitive renewal application is to provide support for protected time for: 1) my mentoring and teaching of junior clinical investigators; and 2) patient-oriented research investigating the role of aldosterone and the mineralocorticoid receptor (MR) in the pathophysiology of cardiovascular (CV) disease. Aldosterone activates the MR and can cause vascular and cardiac inflammation and fibrosis. With support from the first five years of K24 funding, we showed that, in individuals with well-controlled diabetes, treatment with a MR antagonist improves coronary flow reserve, a measure of coronary vascular function. In these same individuals, elevated aldosterone levels were associated with increases in myocardial extracellular volume (ECV), a measure of cardiac inflammation and fibrosis. These findings suggest that, in diabetes, MR activation contributes to impaired coronary flow reserve and increased myocardial ECV; both of which predict increased CV morbidity and mortality in diabetes. In addition, our preliminary data indicates that individuals with metabolic disturbances, increased visceral adiposity and insulin resistance, and HIV have elevated aldosterone levels. Individuals with HIV, well-treated with antiretroviral therapy, have impaired coronary flow reserve, increased myocardial ECV, and increased coronary plaque. They are at increased risk of CV disease as compared to non-HIV individuals. This increased risk of CV disease cannot be accounted for by traditional CV risk factors and no successful treatment strategies exist to complement antiretroviral therapy to reduce CVD risk in HIV. This proposal tests the hypothesis that excess MR activity leads to coronary vascular dysfunction, myocardial inflammation and fibrosis, and increased coronary plaque in HIV. Thus, we will perform a randomized, double blind, placebo controlled trial to demonstrate that treatment with a selective MR antagonist, eplerenone, for 12 months improves coronary flow reserve (Specific Aim 1), myocardial ECV (Specific Aim 2) and coronary plaque (Specific Aim 3). We will utilize sophisticated radiologic techniques (cardiac PET, cardiac MRI and coronary CTA) to quantify these CV outcomes. This research, which is the first comprehensive investigation of MR blockade on CV disease in HIV, aims to provide novel mechanistic insights and a promising strategy for CVD risk reduction in HIV. Moreover, these data should provide critical insight for other non-HIV populations with increased CVD burden. These studies will provide a fertile area for investigation by trainees interested in patient-oriented research and in identifying new, effective treatments of cardiovascular disease in patients with metabolic disorders.

项目概要/摘要此 K24 竞争性续签申请旨在为以下方面的受保护时间提供支持：1) 我的指导和初级临床研究人员的教学； 2) 以患者为导向的研究，调查醛固酮的作用以及心血管（CV）疾病病理生理学中的盐皮质激素受体（MR）。醛固酮激活 MR，可引起血管和心脏炎症和纤维化。在来自的支持下在 K24 资助的前五年，我们发现，在糖尿病控制良好的个体中，采用 MR 拮抗剂可改善冠状动脉血流储备，这是冠状血管功能的一项指标。在这些相同的在个体中，醛固酮水平升高与心肌细胞外容量增加相关 (ECV)，衡量心脏炎症和纤维化的指标。这些发现表明，在糖尿病中，MR 激活导致冠状动脉血流储备受损和心肌 ECV 增加；两者都预测增加糖尿病的心血管发病率和死亡率。此外，我们的初步数据表明，患有代谢紊乱、内脏肥胖和胰岛素抵抗增加以及艾滋病毒导致醛固酮升高水平。艾滋病毒感染者，经过良好的抗逆转录病毒治疗，冠状动脉血流储备受损，心肌ECV增加，冠状动脉斑块增加。他们患心血管疾病的风险增加，因为与非艾滋病毒个体相比。这种增加的心血管疾病风险无法用传统的心血管疾病来解释危险因素和不存在成功的治疗策略来补充抗逆转录病毒治疗以减少心血管疾病艾滋病毒风险。该提案检验了过度 MR 活动导致冠状血管功能障碍的假设，心肌炎症和纤维化，以及艾滋病毒中冠状动脉斑块的增加。因此，我们将执行一个随机、双盲、安慰剂对照试验证明选择性 MR 治疗拮抗剂依普利农，持续 12 个月，改善冠状动脉血流储备（具体目标 1）、心肌 ECV （具体目标 2）和冠状动脉斑块（具体目标 3）。我们将利用先进的放射技术（心脏 PET、心脏 MRI 和冠状动脉 CTA）来量化这些心血管结果。这项研究是首次全面研究 MR 阻断对 HIV 患者心血管疾病的影响，旨在为降低艾滋病毒的 CVD 风险提供了新的机制见解和有前景的策略。而且，这些数据应该为其他心血管疾病负担增加的非艾滋病毒人群提供重要的见解。这些研究将为对以患者为中心的研究和识别感兴趣的受训者的调查提供一个肥沃的领域代谢紊乱患者心血管疾病的新的、有效的治疗方法。